Despite the widespread use of highly active antiretroviral therapy (HAART), HIV-associated neurocognitive disorders remain surprisingly common. Moreover, it is becoming clear that despite HAART, HIV and the closely-related simian immunodeficiency virus (SIV) persist in the brain 'sanctuary', where access of otherwise potent antiretrovirals is limited. However, the mechanisms that establish and maintain HIV infection in the brain despite HAART are largely unknown. The overall goal of this proposal is to explore the role of long-lived brain perivascular macrophages (PVM) as the target cells for SIV infection in the central nervous system during the initial peak viremia and as a major reservoir of virus during chronic infection in the presence of HAART. In our previous studies, we demonstrated that monocyte turnover predicts the onset of AIDS and is correlated with severity of SIV encephalitis in the SIV macaque model. Recently we have reported for the first time depletion of brain PVM in SIV-infected macaques with intrathecally administered liposome-encapsulated bisphosphonates. Our central hypothesis is that HIV infection of PVM contributes to persistent brain infection and inflammation despite HAART and correlates with increased turnover of blood monocytes representing systemic infection of tissue macrophages. The first aim will determine whether eliminating availability and infection of CD4 T cells in acute infection will affect de novo infection of PVM, and whether depletion of PVM in the post-peak phase of acute infection will decrease DNA proviral load in the brain. The second aim will determine whether initiating antiretroviral therapy (ART) after the monocyte turnover increases above pre- infection baseline levels will affect PVM infection, and brain and cerebrospinal fluid viral loads. The third aim will focus on ablating PVM in the setting of ART-treated chronic infection. The research proposed in this application is innovative because it represents an entirely novel departure from the current approach to maintaining viral suppression in HIV-infected patients. Our contribution here will be significant because it is a first step toward the development of therapeutic strategies for targeting virus-infected PVM or inhibiting viral infection of PVM. Once such strategies become available, there is promise that persistent HIV reservoirs could be eradicated from brain and other tissues.